Controlled release of therapeutically active agents, also named biologically active agents, has become essential in treatments of humans and animals. Especially of interest is controlled release of therapeutically active agents locally in a body, such as in tissues or organs for either direct on-site treatment or for systemic uptake.
In recent years, a number of bioresorbable polymers fabricated into product shapes as microspheres, strands, rods and the like have been developed for this reason. The active agent is incorporated into the interior of the polymer product and is after administration to the human or animal body slowly released by different mechanisms. One of the downsides of these products is the laborious process of incorporating the active agents in their interior, that may involve either organic solvents or elevated temperatures. Many active agents will not well survive such circumstances.
An important improvement was found in the use of amphiphilic copolymers, especially triblock copolymers BAB with poly(ethylene glycol) as the central hydrophilic block A flanked by hydrophobic, hydrolysable blocks B. Some of these BAB triblock copolymers have been modified with polymer hydroxyl end-groups comprising fatty acid residues. Said copolymers may form micelles in aqueous solutions and subsequently may form gels at elevated temperatures, such as at 37° C. They may contain at least one therapeutically active agent. For example WO 2011/083086 describes end-capped triblock copolymers that can be used for slow release of therapeutically active agents in human or animal bodies. A disadvantage of these systems is the burst release of therapeutically active agents that may occur after injection of the polymer-drug formulation into a body. Another disadvantage is the limited amount of hydrophobic drugs that can be contained within the hydrogel. Another disadvantage is the limited stability of these hydrolysable triblock copolymers once formulated with water and one or more therapeutically active agents.
US2007/0265356 discloses triblockcopolymers and thermoreversible gels containing said triblockcopolymers with water. The gels also can contain a drug and can be used as slow release system for drugs.
WO2012/131104 discloses triblockcopolymers and thermoreversible gels containing said triblockcopolymers with water. The gels also can contain a drug and can be used as slow release system for drugs. WO99/21908 discloses bioresorbable BAB triblock copolymers having the general structure [polyester]-[polyalkyleneoxide]-[polyester]. The BAB triblock copolymers can be a liquid or a paste. The water insoluble BAB triblock copolymers are blended with water-soluble liquid polymers and a hydrophobic drug.
US2003082234 describes a liquid polymeric composition capable of forming a physiologically active substance containing implant in a living body, said composition comprising a water-soluble biocompatible liquid polyethylene glycol derivative, a biodegradable block copolymer which is insoluble in water but soluble in the said polyethylene glycol derivative, and a physiologically active substance.
US2004001872 describes a composition comprising a BAB block copolymer, a liquid polyethylene glycol and a physiologically active substance.
Disadvantage of the liquid BAB copolymers of the prior art is, that they are used in combination with solvent or liquid polymer additives to make injectable pharmaceutical compositions. In some cases the BAB copolymers have rather high molecular weights and low molecular weight polymers like for example polyethylene glycol are added to make the composition injectable. In other cases the liquid BAB copolymer are used as plasticizers for higher molecular weight block copolymers to make an injectable composition. Addition of these low molecular weight polymers give rise to high burst releases, and an unwanted fast release of the low molecular weight polymer, which may give negative physiological side effects. In yet many other cases water is added to prepare thermoreversible gels, which however show burst release and relative short release times of drugs. None of the known liquid BAB copolymers have been used as such in combination with therapeutically active agents in order to prepare pharmaceutical compositions.